Enolate arylation, enantioselective

To investigate whether an enolate arylation was occurring, the authors prepared enantioenriched cyclopropane substrate 45 and submitted it to the reaction conditions (Scheme 11). After 3 h, all starting material was consumed, and spirooxindole product 46 showed little erosion of enantioselectivity. Furthermore, the kinetic isotope effect was determined via parallel reactions to be 3.9, identifying C-H cleavage as a rate-determining step. This observation is not consistent with an enolate-like pathway. Furthermore, the use of a weak base (K2CO3) makes the enolate pathway quite unlikely. 

The arylation of enolates based on chiral auxiliaries has by far not reached the relevance of the alkylation procedures. For the arylation, enantioselective catalysis (cf. Section 5.2) became much more relevant than the auxiliary approach. As the arylation is based on palladium catalysts, it is as elegant as obvious to use a ligand at the noble metal as the chiral inductor. 

Scheme 5.47 Enantioselective palladium-catalyzed enolate arylation of racemic aminomethylene ketones 143 mediated by chiral ligands 144.

The concept of enantioselective intramolecular enolate arylation was also applied to obtain indanyl aldehydes 168, according to a protocol of Buchwald and Garda-Fortanet, from aryl bromides 167. A screening of ligands revealed the... 

Scheme 5.53 Enantioselective intramolecular enolate arylation of racemic ortho-bromoanilides 161, 163, and 165.

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

Catalyst performance was far superior to the corresponding BINAP or Me-Du-Phos systems, with both conversions and selectivities being higher. The hydrogenation of enol ethers using Rh-PennPhos catalysts has been reported in a patent by Zhang [67d]. Under mild conditions, high enantioselectivities were obtained (73-94% ee) for 1-aryl-l-methoxy-ethene derivatives 121, compared to Me-DuPhos (40-73% ee) and BINAP (46-48% ee). 

A different approach towards titanium-mediated allene synthesis was used by Hayashi et al. [55], who recently reported rhodium-catalyzed enantioselective 1,6-addition reactions of aryltitanate reagents to 3-alkynyl-2-cycloalkenones 180 (Scheme 2.57). In the presence of chlorotrimethylsilane and (R)-segphos as chiral ligand, alle-nic silyl enol ethers 181 were obtained with good to excellent enantioselectivities and these can be converted further into allenic enol esters or triflates. In contrast to the corresponding copper-mediated 1,6-addition reactions (Section 2.2.2), these transformations probably proceed via alkenylrhodium species (formed by insertion of the C-C triple bond into a rhodium-aryl bond) and subsequent isomerization towards the thermodynamically more stable oxa-jt-allylrhodium intermediates [55],... 

MeOC6H4, respectively. The titanium enolates were converted into silyl enol ethers 54 by treatment with chlorotrimethylsilane and lithium isopropoxide. Additionally, cyclic enones lb and Ic, and linear enones Id and le, are also good substrates for the asymmetric conjugate addition of phenyltitanium triisopropoxide, giving the corresponding arylation products with over 97% enantioselectivity. 

Later in 2007, Gong utilized If and saturated derivative 2 in a direct Mannich reaction between in situ generated N-aryl imines and cyclic ketones as well aromatic ketones (Scheme 5.3) [10], It was found that electron poor anilines as coupling partners gave the highest enantioselectivities. The authors postulate that acid promoted enolization of the ketone forms the reactive enol which adds to the protonated aldimine. 

Stephen L. Buchwald at MIT has reported (Org. Lett. 2004, 6, 4809) a complementary approach. Enantioselective conjugate reduction of the inexpensive 3-methylcyclopentenone 4 led to the silyl enol ether 5, Pd-mediated coupling of which with the aryl halide gave the product 6. 3-Methylcyclohexenone gave the analogous product in 84% . 

Buchwald has designed a hindered dialkylphosphino-binaphthyl ligand (3) that is much more active than the original ligand for asymmetric arylation of ketone enolates. Reactions occur at room temperature using only 2 mol % catalyst with enantioselectivities up to 94% [41]. Additionally, the Buchwald group has developed an electron-rich monodentate ligand (4) capable of vinylation of ketone enolates with up to 92% ee [42]. 

Enanantioselective aldol reactions. Divalent tin enolates of aldehydes and aryl ketones generated with tin(II) triflate undergo aldol condensation with aldehydes to form aldols.2 The reaction is highly enantioselective if conducted in the presence of chiral diamines derived from (S)-proline, such as l.3... 

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